In-person Flash Talk & E-Poster Presentation 34th Lorne Cancer Conference 2022

High throughput cell morphology-based drug screen in breast and prostate cancer reveals novel AR agonists (#13)

Amy Dwyer 1 , Jean M Winter 1 2 , Susanne Ramm 3 4 , Karla J Cowley 4 , Nicholas Choo 5 , Jennii Luu 4 , Stephen M Pederson 1 , Richard D Iggo 1 , Luke Selth 1 2 , Elgene Lim 6 , Gail Risbridger 3 5 , Renea Taylor 3 , Kaylene J Simpson 3 4 , Theresa E Hickey 1 , Wayne D Tilley 1
  1. The University of Adelaide, Adelaide, SA, Australia
  2. Flinders University of South Australia, Adelaide, SA, Australia
  3. Sir Peter MacCallum Dept of Oncology, University of Melbourne, Melbourne, VIC, Australia
  4. VCFG, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  5. Dept of Anatomy and Developmental Biology, Monash University, Clayton , VIC, Australia
  6. Garvan Institute of Medical Research, Sydney, NSW, Australia

Breast (BC) and prostate cancer (PC), the most common invasive cancers in women and men, are hormone-dependent with remarkable underlying biological similarities. Both cancers are driven by oncogenic sex hormone receptor (SHR) activity i.e. estrogen receptor (ER) and androgen receptor (AR), respectively. The therapeutic strategy for both diseases is to eliminate activity of the offending hormone and/or its receptor i.e. endocrine therapy (ET). In both diseases, ET prolongs life, but disease progression is common and invariably fatal.
We have shown that AR agonism with either the natural AR ligand (DHT) or a selective androgen receptor modulator (SARM) potently inhibits endocrine-sensitive and -resistant BC growth. While this provides a compelling rationale for AR activation as a therapeutic strategy in BC, SARMs are less potent than DHT in our studies of endocrine-resistant BC, and testosterone-derivatives are associated with liver toxicity, making these drugs unattractive therapeutic options. Hence, there is an urgent need to develop new safe AR agonists with the requisite selective growth inhibitory activities. Emerging evidence suggests that AR agonists are also effective in inhibiting growth of PC.
In this study, we screened >3,000 novel SHR ligand analogues across a suite of endocrine-sensitive and -resistant BC and PC cell lines (n=4 each) to identify novel AR agonists with growth inhibitory activity. “Hits” were selected by >30% growth inhibition and morphological changes quantified by a Mahalanobis distance incorporating nuclear, whole-cell and cytoskeletal immunofluorescence. Candidate ligands that promoted changes in morphology similar to that induced by AR agonists but not AR antagonists, ET or chemotherapies were prioritised. Live-cell imaging of patient-derived 3D organoids further stratified lead compounds with potent growth inhibitory activity. Following a medicinal chemistry triage, compounds were prioritised for characterisation of their effects on AR signalling in BC and PC and growth inhibitory activity in vivo, with view to progressing a lead compound to develop a novel AR agonist as a bona fide ET for BC and PC.